| Autor: |
Kingsbury WD; Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939., Pendrak I, Leber JD, Boehm JC, Mallet B, Sarau HM, Foley JJ, Schmidt DB, Daines RA |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1993 Oct 29; Vol. 36 (22), pp. 3308-20. |
| DOI: |
10.1021/jm00074a012 |
| Abstrakt: |
Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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